Manipulating brain may ease pain of drug withdrawal

"Most research that studies drug addiction is focused on the reward pathway because that is the reason you start to take drugs, but people who really get addicted also take drugs to get rid of the withdrawal effect. This is especially important in opiate addiction," says Xiaoke Chen. (Credit: Daniel Cely/Flickr)

In addition to the desire to experience a “high,” one of the obstacles drug addicts encounter is the difficulty of overcoming a myriad of harsh withdrawal symptoms, including anxiety, depression, nausea, vomiting, and diarrhea.

When people learn to associate the loss of drug use with the pain of withdrawal, it can create an urge to use that is as strong as the “high” itself, making it even more difficult to quit.

Some of these symptoms can be partially managed, but new research holds the promise of a more effective treatment for drug addiction by suppressing urges at their origin within the brain.

A recent discovery has both pinpointed and controlled nerve centers in the brain that react to this aversive withdrawal stimuli. In a new study, scientists were able to eliminate negative reactions to opiate withdrawal symptoms in morphine-dependent mice.

“Most research that studies drug addiction is focused on the reward pathway because that is the reason you start to take drugs, but people who really get addicted also take drugs to get rid of the withdrawal effect. This is especially important in opiate addiction,” says lead investigator Xiaoke Chen, assistant professor of biology at Stanford University.

The research, published in the journal Nature, began by studying the nucleus accumbens, a group of neurons in the brain that is commonly associated with drug reward. Other studies, however, have also shown that it responds to aversive stimuli, including drug withdrawal.

To further investigate this behavior, researchers used fluorescent proteins to illuminate brain centers and view the pathways that connect them. The experiment highlighted a particularly clear link between the nucleus accumbens and a small group of cells in the paraventricular nucleus of the thalamus (PVT).

The scientists then tested the link between the nucleus accumbens and the PVT using the technique of optogenetics that makes use of light-sensitive molecules that can convert photons into electric signals, the same process that occurs in the human eye. These molecules are introduced into a specific nucleus of the brain and can be used to turn neurons on or off via light from an optical fiber, thereby allowing specific manual control of neural activity.

Results of this testing showed the pathway to activate aversive reactions to drug withdrawal rather than reward. Chronic drug use strengthens the PVT-to-nucleus-accumbens pathway, Chen says, and this strengthening might be responsible for the heightened withdrawal responses that accompany addiction. Using optogenetic tools, the scientists were then able to revert the pathway to its original synaptic strength, effectively erasing the effects of the drug. Although the research was conducted in mice, the findings suggest that reprogramming this circuit holds promise for treating opiate addiction in people.

“This is a knowledge-guided treatment. We not only identified a new pathway, but we actually established the causality between the plasticic change in this single synapse and opioid withdrawal symptoms,” Chen says. “Drugs affect many places throughout the brain, but here we manipulate this single synapse and can get rid of this drug effect.”

The PVT-to-nucleus-accumbens pathway is also responsible for controlling behavioral response to nondrug aversive stimuli. In the future, Chen hopes that his research will lead to safer, guided treatments for drug addictions and other, nondrug related behaviors. Exaggerated aversive response to external stimulation is a common phenomenon for many people dealing with anxiety and depression.

“That’s one of the reasons they try to avoid social interaction,” Chen says. “They don’t want to get hurt. But I am hopeful that this work will provide scientists with the insight to help people overcome these afflictions.”